8
CgA may also derive locally from myocardial production, notably in ventricles of
heart failure patients (Pieroni et al. 2007 ). The full-length CgA dilates coronaries
and induce negative inotropism and lusitropism in the ex vivo perfused rat heart at
0.1–4 nM, but not at higher concentrations (Pasqua et al. 2013 ). Of note, analysis of
the perfusates showed that exogenous CgA was not cleaved by the heart, suggesting
that the myocardial effects were induced by the circulating, full-length protein.
However, the same study demonstrated that physically and chemically stimulated
rodent hearts could proteolytically process the intracardiac, endogenous CgA into
fragments (Glattard et al. 2006 ). Moreover, the increased plasma levels in chronic
heart failure (Ceconi et al. 2002 ), its over-expression in human dilated and hypertro-
phic cardiomyopathy (Pieroni et al. 2007 ) and the observation that the circulating
CgA provide prognostic information on long-term mortality, independent of con-
ventional risk markers in acute coronary syndromes (Jansson et al. 2009 ), all point
to a significant role of CgA in human cardiovascular homeostasis. Hence, the sys-
temic and intracardiac fates of full-length CgA and its fragments imply intriguing
new aspects of the myocardial handling of CgA under normal and pathophysiologi-
cal conditions.
To what extent the elevated circulating levels of CgA, VS-I and catestatin together
are beneficial or detrimental to the failing heart, remains unanswered. Taking into
account that an inflammatory response is caused by myocardial injury arising from
ischemic reperfusion (Anaya-Prado and Toledo-Pereyra 2002 ), a link between
plasma CgA and/or its fragments in cardioprotection seems plausible. For instance,
it is well established that the human recombinant VS-1 (hrSTACgA1-78) precondi-
tions the rat heart against myocardial necrosis arising in response to reperfusion of
the ischemia-injured tissue, presumably involving the endothelial/endocardial ade-
nosine/nitric oxide signaling pathway (Cappello et al. 2007 ). In contrast, catestatin,
being without pre-conditioning effects, may modulate reperfusion injury during the
post-ischemic reperfusion period (Penna et al. 2010 ; Penna et al. 2014 ). Hence, it
seems likely that N- and C-terminal CgA fragments arising from processing of the
circulating and intracardiac pools of CgA in species-specific patterns, may exert
beneficial effects, not only under experimental conditions in animal models (Pasqua
et al. 2013 ), but also in the failing human heart in situ.
Although the two structurally different CgA peptides, VS-I and catestatin, both
exert negative myocardial inotropy, non-competitively inhibiting the
β-adrenenoceptor on cardiomyocytes (Tota et al. 2008 ; Angelone et al. 2008 ), these
apparently converging effects on the heart may be less puzzling when realizing that
these two peptides may not reach peak concentrations in the same frame of time
(Crippa et al. 2013 ). The thrombin.induced C-terminal processing of the anti-
angiogenic, full length CgA into a catestatin-containing angiogenic fragment point
to a functional rationale, namely maintaining protection of the heart against exces-
sive adrenergic stimlation by CA, whether by VS-I or catestatin, regardless of the
quiescent or stimulus-activated state of the vasculature.
K.B. Helle